WO2024028469A1

WO2024028469A1 - Method for determining a substance concentration and detector device

Info

Publication number: WO2024028469A1
Application number: PCT/EP2023/071620
Authority: WO
Inventors: Klaus Flock; Timm MUELLER
Original assignee: ams Sensors Germany GmbH
Priority date: 2022-08-04
Filing date: 2023-08-03
Publication date: 2024-02-08

Abstract

The invention concerns a method for determining a substance concentration in a sample (2) comprising liquid containing particles, wherein a refractive index of the liquid is dependent on a concentration of the substance dissolved therein and a density of particles in the liquid is substantially constant. The method comprises detecting two different light components that are characterized by a different path length (D1,D2) through the sample (2) and obtain two signals representing light intensity of the scattered light through the sample (2) therefrom. A substance concentration is derived from the first and second intensity signals, in particular from a ratio of the first and second intensity signals.

Description

METHOD FOR DETERMINING A SUBSTANCE CONCENTRATION AND DETECTOR DEVICE

The present application claims priority of German patent application DE 10 2022 119 565 . 1 dated August 04 , 2022 , the disclosure of which is incorporated herein by reference in its entirety .

The present invention relates to a method for determining a substance concentration in sample containing particles in a liquid, in particular glucose in blood, wherein a refractive index of the liquid is dependent on a concentration of the substance dissolved therein . The invention also relates to a detector device .

BACKGROUND

The current standard for blood glucose measurement often uses an invasive technique in which a small amount of blood is drawn, and subsequent electrochemical analysis is performed using a handheld device . This method is not suitable for continuous monitoring because for each measurement , the finger must be pricked to obtain a fresh blood sample .

A more recently developed technology uses a button that sits on the skin and misses interstitial fluid in parts of the subcutaneous adipose tissue with a small , needle-like sensor . However , the needle penetrates permanently into the skin .

Besides these invasive methods , there are also non-invasive methods based on optical IR measurements or Raman spectroscopy . While in the first case , a suitable choice of emitter and detector leads to difficulties , an approach based on Raman spectroscopy is challenging due to the very poor signal-to-noise ratio .

In this respect , there is a need for a method that can detect a substance in a liquid in a simpler way and allows for a continuous measurement .

SUMMARY OF THE INVENTION This and other obj ects are addressed by the subj ect matter of the independent claims . Features and further aspects of the proposed principles are outlined in the dependent claims .

Complementing some other ideas that are based on an angle dependent scattering, the present idea relies on the evaluation of the scattering signal , also referred to as perfusion index, which has been found by the inventors to also depend on the blood glucose concentration .

Due to scattering and absorption of light , which is initially directed towards the skin and may subsequently propagate through portions of shallow- and/or deeper lying tissue , which in turn hosts a network of blood vessels , the amount of light that re-emerges at the skin-to- ambient interface some distance from the entry point will vary according to the optical path length ( distance ) travelled in blood . The path length is referred to as "blood optical path length ( BOPL ) " . The BOPL is affected among other things by the beating of the heart , but essentially by the location at which the scattered light signal is measured and more precisely from the distance between the location of the incident light and the location of the scattered light . More particular, it has been found that the amount of scattered light is dependent on the distance between the incident position ( the location on the sample at which the light enters the sample ) and the position on the sample at which the scattered light is detected . Consequently, scattered light received at two different locations behave differently . This difference is caused by the path through the liquid containing the substance whose concentration is to be determined .

Assuming a constant concentration, the scattering behaviour follows a well-known principle and is merely constant , but a changing concentration over time also leads to a behaviour from which the concentration or at least a change of the concentration can be derived . It has been found that a change in concentration of glucose in blood ( or any other substance in blood) causes a measurable change of the scattering . Obtaining the amount of light at different locations from the spot of the incident light and deriving a ratio from those two obtained signals , one can obtain a value that is against any systematic error and changes directly with the substance concentration . When the time between the two measurements at the different locations is short , the effect of heartbeat causing the BOPL to change is neglectable . On the other hand, one may also take into account not only the signal ratio at two different locations , but also evaluate the signal changes caused by the heartbeat , i . e . by evaluating the change of the BOPL due to different blood pressure . This is referred to as perfusion index and specifically addressed in application XXX, which is incorporated herein by reference in its entirety .

According to Beer-Lambert ' s law, the absorption of light in blood is largely determined by the presence of Hemoglobin within the erythrocytes , as well as the cumulative BOPL . Under the assumption that the density of erythrocytes does not change during the measurement period and at the slightly different locations , one can say that light propagating nominally through the more or less transparent blood plasma, undergoes scattering at the red blood cells , such that the cumulative BOPL from entry point to the two detection points , both of which are fixed by the device configuration, may depend on the scattering characteristics in the sense of a random walk, i . e . , it will become a stochastic process .

Consequently, the detected light is primarily a result of the direct interaction and particularly the scattering between light and erythrocytes between the incident light spot and the detection location .

It has now been observed that for a human test subj ect under steadystate conditions and constant blood glucose levels , the individual signals and particularly the ratio of both signals is substantially constant , neglecting for the time being any influence of the varying blood pressure caused by the heartbeat . This characteristics may inherit some benefits , as one can use a steady state as a reference value , such that a single measurement of the perfusion index allows to derive a blood glucose change therefrom. When the blood glucose level increases , the properties of the blood plasma and more particularly the refractive index of the plasma changes . As a result , the difference between the refractive indices of the erythrocytes and the blood plasma decreases , which will cause a decreases of scattering light .

Likewise , a decrease in the glucose increases the difference between the refractive indices of the erythrocytes and the blood plasma causes an increase in scattering .

This is explained in a model , in which scattering is mainly caused by diffraction differences , thus in a transparent medium, in which the refractive indices of the liquid and the scattering particles were the same , no scattering would be observable , since light would simply propagate through the medium without interaction . However , once there is an index mismatch, some light is being scattered ( e . g . , backwards ) by the particles and thus can be distinguished from the surrounding ambient , i . e . , plasma . The higher this index difference becomes , the stronger the scattering effect will be .

The effect is observable not only for glucose , but generally for any substance in a liquid containing particles , whereas the particle size is approximately in the wavelength of the light and the substance concentration influences the refractive index of the liquid . A s killed person will therefore understand that the principle disclosed herein with regards to Photoplethysmography, and glucose measurement can be applied in a more general way and implemented for various kinds of measurement determining the concentration of a substance in a particle containing liquid .

In case of glucose in blood or more generally, any varying substance in blood affecting the refractive index of the blood plasma will cause a variation of scattered light in the receiving detectors . This is due to the different BOPL that result in different scattering, which in turn are dependent on the substance concentration in the blood . Hence , an increase of the blood glucose level causes a decrease in the scattered signal and conversely, when the blood glucose level decreases , the scattering increases , resulting in a direct correlation of the optical DC/DC ratio of two scattering locations spaced apart .

In addition, the different glucose level also changes the BOPL during PPG measurements causing a varying AC-to-DC ratio of Photoplethysmography and blood glucose concentration . It is observed in both cases ( that is for very quick measurement , in which the blood pressure due to hard beat is substantially constant and in longer measurement including the PI and the modulation depth of a PPG that an increase in the DC/DC ration at two different locations and the modulation depth due to glucose in the plasma corresponds to an effective increase in the difference between maximum and minimum BOPL .

The observation holds for different wavelength of the incident light and the correlation exists for green, red, and near-IR wavelengths . In fact , the mechanism is observable for a relatively wide range of wavelengths from the visible to NIR portions of the spectrum, in agreement with Lorenz-Mie scattering theory .

Consequently, evaluation of changes and variations of the scattering between different distances alone and if needed in consideration of the modulation depth in Photoplethysmography over a longer period of time provides an opportunity for detecting -- non-invasively and directly -- the properties of blood only, without many of the complications arising from signals originating within the interstitial fluid and other layers or portions of tissue and skin .

In some aspects , the inventors propose a method for determining a substance concentration in a sample comprising liquid containing particles , in particular glucose in blood, wherein a refractive index of the liquid is dependent on a concentration of the substance dissolved therein and a density of particles in the liquid is substantially constant . The method comprises the step of emitting a , -in particular periodic- first light pulse of at least one wavelength onto a first location of the sample containing the liquid . A first light component scattered by the sample is detecting at a second location, the second location being distanced from the first location by a first distance . Likewise at a third location a second light component scattered by the sample is detected . The third location is distanced from the first location by a second distance different from the first distance .

It is suitable to further detect any ambient light and other effects to compensate for such signal portions later on . Consequently, a third light component during a duration, where no light is emitted is detected at least at one of the second and third location . The detection of the third component is set to a time frame , where no artificial light is emitted . The detected signals may be pre-processed, . i . e . digitized using an AD converter, in particular having a converter having at least 14 bits of resolution . Further, a first intensity signal is obtained from the first light component and the third light component . In a similar manner , the second light component is processed to obtain a second intensity signal from the second light component and the third light component . In some instances the third light component can be averaged prior of being processed with the first and second light components to reduce smaller variations in the third light component .

The substance concentration can be derived from the first and second intensity signal , in particular from a ratio of the first and second intensity signals as indicated above . In this regard, it is suitable for example to build the ratio in such way, that the intensity signal corresponding to the smaller distance is the nominator, while the light intensity signal corresponding to the longer distance forms the denominator .

In an alternative method for determining a substance concentration in a sample comprising liquid containing particles , the detected scattered light components correspond to different path lengths through the sample , in the previous aspect such different path length can be achieved by detecting the light components at two different location, while the incident light does not change . Alternatively, one may emit a, -in particular periodic- first light pulse of at least one wavelength onto a first location of the sample containing the liquid . Likewise , a -in particular periodic- second light pulse of at least one wavelength is emitted onto a second location of the sample containing the liquid . In other words , two light pulses are emitted onto the sample , but at different locations .

At a third location, a first light component scattered by the sample is detected, the third location being distanced from the first location by a first distance . Similar at the third location a second light component scattered by the sample is detected, the third location being distanced from the second location by a second distance different from the first distance . Hence , the overall path length, that is the length of the light through the sample is different . A third light component may also be detected at the third location during a duration, where no light is emitted .

The subsequent processing is similar as previously mentioned and includes obtaining a first and second intensity signal from the first light component and the third light component and from the second light component and the third light component , respectively . The substance concentration can be derived from the first and second intensity signal in the same manner , for instance from a ratio of the first and second intensity signals . In this regard, it may be suitable to emit the first and second light pulses at different times such that they do not interfere with each other . Alternatively they can be emitted with slightly different wavelength, such that their detection at the third location is distinguishable .

Both proposed principles result in a robust ratio directly correlated to the change of the substance concentration over time . Systematic signal variations are compensated for due to the forming of the ratio .

It has nonetheless surprisingly found that it is not necessary to conduct two measurements to obtain the concentration or the concentration change in a liquid . Rather , one can define a reference value and then conduct a single measurement , that is a measurement at a given distance . Using the reference , one is able to derive the substance concentration or changes thereof . Consequently, the inventor proposes a method comprising the steps of obtaining a reference value associated with or corresponding to at least one of a first modulation depth, or one of the first and second intensity signals or a signal derived therefrom .

For example , one of the measurements is then replaced by the reference value , which can be obtained by several means prior to the actual measurement . In this regard, it is understood that the reference value may comprise not only the intensity signal but can also refer to any value , from which the reference concentration of a substance or a signal to be processed subsequently can be meaningful derived . Consequently, the term reference value shall be understood as being equivalent to any value from which the substance concentration or the intensity signal can be derived .

In accordance with the proposed method, the substance concentration or a change in the substance concentration is derived from the changes between the reference value and the respective other intensity value or a value derived therefrom.

The reference value and also characteristics from a curve corresponding to the change of the intensity signal in relation to the substance concentration or the blood glucose level are dependent on various factors . Hence , one may utilize those factors , when obtaining the substance concentration . These include , but are not limited to the age , size , weight , gender, body mass index and s kin type . Particularly, skin type can be used not only to adj ust the processing of the respective intensity signals , but also adj ust the wavelength of the emitted signals .

In some aspects , the reference value is a statistical value obtained as a general normalized intensity signal ( different from zero ) from a plurality of different previous measurement . Those may take one or more of the above parameters into account to obtain a small range with certain confidence level i . e . 2o or 3o .

Some aspects concern the acquisition of data and the duration of the measurement . In this regard, it should be noted that the heartbeat will periodically change the blood volume , which then can affect the amount of scattered light . As already mentioned herein, one can obtain the perfusion index, that is the AC portion of a PPG signal over time , and the perfusion index itself may vary with a changing glucose level .

Consequently, in some aspects , in which a longer measurement takes place covering one or more of such heartbeats , the detected first and second light component may contain an AC portion corresponding to the variations of obtained signal due to the external excitement ( e . g . the heartbeat ) and a DC portion . The DC portion may correspond in some instances to the averaged signal obtained during the longer measurement . Likewise do the first and second intensity signals includes such AC and DC components . A substance concentration can now be derived by either evaluating the AC portions of the two intensity signals , the DC portions of the two intensity signals or a combination thereof . For example , in some aspects the substance concentration can be derived by the ratio of the AC portions of the first and second intensity signals . Alternatively, substance concentration can be derived from a ratio of the AC/DC portions of the respective first and second intensity signals . i . e .

One may also utilize certain factors to adj ust to the s kin type or other parameters .

Some further aspects concern the acquisition of data . For example , the first and/or second light pulse may comprise a periodicity between 20 Hz and 500 Hz , an in particular between 50 Hz and 200 Hz and particular above 75 Hz . Hence , an individual measurement is taken usually in a relatively short time span, in which a change of the substance concentration but also an external slower trigger ( e . g . a heartbeat ) does not affect the individual measurement . Each individual measurement is referred to as a sample , and several samples can be combined into a single value .

However , several of such measurements may be influenced by the external parameter . If the frequency is high and the number of measurements taken is low, one can usually assume that a slow varying parameter , like the change of blood volume due to heartbeat does not significantly affect the measurements . Otherwise , this can be taken into account by evaluating the effect of such slow varying parameter .

In addition, the first and/or second light pulse comprises a duty cycle in the range of 1 /20 to 1/5 of the period . This will reduce the overall power consumption but is still sufficient to obtain the necessary information . As a result , the method can be implemented in a portable device , like a mobile phone , a watch or a portable medical device .

In some instances , two light pulses are emitted onto different locations of the sample , and the back scattered light is retrieved from a single location . In such cases , the two light pulses may be generated time interleaved, whereas the time difference between emitting the first light pulse and emitting the second light pulse is less than 1 second and particularly between 10 ms and 250 ms and more particularly between 30 ms and 100 ms . Generally, the time difference between emitting the first and second light pulse should be substantially shorter to avoid being affected by a slow varying external parameter like for example a heartbeat .

Some aspects concern the position of the respective emitting and detecting location . In some aspects , a direction from the first location to the second location is different compared to a direction from the first location to the third location . This may prevent to fail in the measurement if one of the two locations is obstructed . Further, detecting light components from a plurality of different location provides the option of compensate noisy or undesired signal components , different optical behaviour on the location and the like . The duration during the third light component is detected is usually longer than the duration for the detection of the first and/or second light components . The third light component in this regard may represent mainly the undesired components coming from, but not limited to , ambient light signals , noise , variations in the external parameters like temperature or humidity and the like .

Another aspect concerns a detector device for determining a substance concentration in a sample comprising liquid containing particles . The detector device comprises a housing with at least one optoelectronic component and at least one light detecting component arranged therein . The housing comprises exits windows for accessing the at least one optoelectronic component and at least one light detecting component . Furthermore the at least one light detecting component within the housing is optically separated from the light emitting device .

The at least one optoelectronic component is configured to emit light through an exit window onto a sample . Accordingly, the sample is usually placed above the exit window in the beam path of the light emitted by the at least one optoelectronic component . It is useful to place the sample tight onto the exit window to reduce any ambient light from reaching the surface of the sample . Consequently, in some aspects , the housing and/or the exit is configured to follow the shape of the sample or at least adj ust such that entry of ambient light is reduced .

Similar configurations may be applied to the entry window in front of the at least one detector component . The entry window should be tight on the sample to avoid ambient light from getting through the entry window and reaching the detector component .

The at least one detecting component of the detector device according to the proposed principle is configured to detect two light components corresponding to emitted light scattered through the sample , wherein said two light components correspond to different path length of light travelling through the samples . In particular one path length is longer than the second path length . A control circuit is coupled to the at least one optoelectronic component and at least one light detecting component .

The control circuit is configured to obtain a first signal from the at least one detecting component corresponding to a detected first light component , a second signal from the at least one detecting component corresponding to a detected second light component and a third signal from the at least one detecting component corresponding to a detected third light component . The third light component is detected while the at least one optoelectronic component is not emitting . Hence the third light component may include for example any ambient light , noise or other undesired component . The control circuit is configured to derive a first intensity signal from the first and third signal and a second intensity signal from the second and third signal . Finally, said control circuit is further configured to derive a substance concentration from the first and second intensity signal , in particular from a ratio of the first and second intensity values .

The detector device can be implemented in a hand-held or a mobile device . It is possible to utilize already existing setups , which are suitable for PPG measurements , blood pressure or oxygen concentration for example . In some aspects , a distance between the at least one optoelectronic component and a first of the at least one light detecting component is different to a distance between the at least one optoelectronic component and a second of the at least one light detecting component . Alternatively, a distance between a first of the at least one optoelectronic component and the at least one light detecting component may be different to a distance between a second of the at least one optoelectronic component and the at least one light detecting component . Both implementations will ensure that the optical path length the signal is travelling through the sample is different , which will cause different amount of scattering thus leading to a measurable difference .

As an alternative to an evaluation using the two or more intensity signals , one may utilize a reference value . Hence , only a single measurement is required to determine a substance concentration or a change in the substance concentration in the sample . In such alternative , the control unit is configured with a memory storing one or more reference values . The control unit is further configured to determine a substance concentration or a change in the substance concentration in the sample utilizing the reference value and one of the first and second intensity signals or values derived therefrom .

Said reference value is associated with or can correspond to -as previously mentioned above- different characteristics including, but not limited to an intensity signal at a given distance , or a signal derived therefrom . It can correspond to a normal level at said distance , which may be individual or obtained from statistical value or derived over a longer period of time , e . g . a long measurement time of the respective user . Furthermore , the reference value is associated with or can correspond to a function that links the intensity signal with the perfusion index, with the modulation depth or any other signal characteristics . Likewise , such function is equivalent to a function that links the intensity signal to glucose level , to the perfusion index or any other signal characteristics .

The reference value can be derived as mentioned above , i . e . individually for each person or from a plurality of measurements as a statistical normalized value or function . This can take at least one of body mass index , age , gender , height and weight and s kin type into account .

In some aspects the at least one optoelectronic component and the at least one light detecting component are arranged substantially in the same plane . In such implementation, the detecting components may detect light components that are backscattered from the light emitted onto the sample . In some other instances , the at least one optoelectronic component and the at least one light detecting component are arranged in two different , optionally substantially parallel planes , wherein optionally, the sample is placed in a light path between the two different planes . This implementation will therefore detect light components that are transmitted through the sample , although even such light components may be scattered through the sample . Combinations for both are possible , e . g . the planes of the light emitting component and the light detecting component can be inclined to each other .

In some further aspects , the at least one light detecting component comprises a light filter comprising a low transmittance in a frequency spectrum different from a light spectrum emitted by the at least one light emitting component . This measure will further reduce ambient light portions in the detected component thereby improving the quality of the detected component . Although the detector device presented herein is only illustrated with regards to its functionality concerning the determination of substance concentration, one may note that various implementations are possible . In this respect , the control unit or portions thereof does not need to be implemented within the housing itself containing the emitter and the detector but can be located separately therefrom. In some aspects , the control unit is implemented in a separate device distances from the housing itself . Communication between the emitter and detectors and the control unit as described above is facilitated for example by a wireless communication . This will allow for example to realize a master slave configuration, in which the control unit request measurement to be taken on regular basis . Furthermore , the control unit may be implemented largely in Software , for example as an app executed on a mobile device , whereas the remaining portion of the detector device are implemented in a separate housing .

In some aspects , the housing ( or the detector device in more general terms ) is implemented as a ring , earbud, watch or any other wearable , that may fit in some aspects into a user' s usual environment and can be carried continuously . Said ring, earbud, watch or any other wearable is in communicative connection with the control unit or a mobile or any other device implementing the control unit . The ring, earbud, watch or any other wearable may cover a larger portion of the user' s s kin, e . g . wrap around the finger, clipped to the ear from both sides and the like . They may contain several emitters and detectors at various location, thus allowing not only to measure at one spot but at several at once or subsequently . As a result thereof , skin irregularity or other issue can be overcome and the overall measurement quality improved .

Apart from devices and handheld devices , other applications are possible . For example , the detector device can be implemented in medical devices or laboratory equipment , e . g . for test and measurement purposes . Those devices again can be stationary or mobile .

Some more aspects concern mobile displays in which the detectors are directly implemented . In such applications , the display LEDs e . g . for the red and green colour can be used as emitter in accordance wrth the proposed principle . A finger is placed directly on the display surface and then illuminated by the display for obtaining the first and/or second signal . Likewise , the proposed principle can be implemented in VR or AR glasses and devices . Another application concerns safety issued, e . g . during certain labour work but also during driving and the like . It is possible to implement such detector devices in accordance with the proposed principle in a car, e . g . on the steering wheel to obtain the intensity signals and the changes thereof during driving . Thrs enables for example warnings to the driver of potentral health threats while driving .

SHORT DESCRIPTION OF THE DRAWINGS Further aspects and embodiments in accordance with the proposed principle will become apparent in relation to the various embodiments and examples described in detail in connection with the accompanying drawings in which

Figure 1 shows the relation of the several intensity signals at different wavelengths and differen t path length in accordance with some aspects of the proposed principle ,

Figures 2 illustrates a first embodiment for a light emitter and detector according to some aspects of the proposed principle ;

Figure 3 shows a second embodiment for a light emitter and detector according to some aspects of the proposed principle ;

Figure 4 to Figure 9 illustrate several signal time-diagrams to show the influence of wavelength and other parameters in accordance with some aspects of the proposed principle .

DETAILED DESCRIPTION

The following embodiments and examples disclose various aspects and their combinations according to the proposed principle . The embodiments and examples are not always to scale . Likewise , different elements can be displayed enlarged or reduced in size to emphasize individual aspects . It goes without saying that the individual aspects of the embodiments and examples shown in the figures can be combined with each other without further ado , without this contradicting the principle according to the invention . Some aspects show a regular structure or form. It should be noted that in practice slight differences and deviations from the ideal form may occur without , however, contradicting the inventive idea .

In addition, the individual figures and aspects are not necessarily shown in the correct size , nor do the proportions between individual elements have to be essentially correct . Some aspects are highlighted by showing them enlarged . However , terms such as "above" , "over" , "below" , "under" "larger" , "smaller" and the like are correctly represented with regard to the elements in the figures . So it is possible to deduce such relations between the elements based on the figures .

Figure 1 is a diagram illustrating the relationship between the optical path length through the respective sample and the strength of the scattered light through a sample . The x-axis of the diagram shows the distance of the optical path length . The optical path length is defined as the distance the light travels through the sample , that is between the location of the incident spot on the sample and the location at which is backscattered light is detected . Distance 0 represents a spot on the sample equal to the incident location as well as the location at which backscattered light is detected . The y-axis comprises an arbitrary logarithmic value scale of the received signal .

The illustration in Figure 1 includes three curves referred to as KI , K2 and K3 . They represent the measurements at the respective different distances given at different wavelength . In particular , curves KI illustrates the backscattered signal at a wavelength in the infrared spectrum, the curve K2 shows a signal of backscattered light from a red light source and curve K-3 illustrates the same situation for a green light source . Its seems that the relationship for curves KI and K2 is substantially linear and more particular both curves show a linear decrease over a distance of 5 mm starting from an initial distance at 2mm. the decrease depends on the distance between the incident spot and the detected spot and is substantially linear over the measured distance between two mm and 7 mm, respectively . In contrast to those curves , measurement curve K3 comprises a stronger decrease over the same given distance . This is partially explainable by a higher absorption or scattering of the green wavelengths throughout the distance . The interaction for green light is generally stronger than for red or infrared light .

The incident light provided by the respective emitter is emitted onto a specific location on the sample . The incident light now travels through the sample and is on its way scattered and/or partially absorbed by the particles in the sample . While the amount of absorption is mainly constant , the scattering is dependent on the substance concentration, which changes the refractive index difference between the liquid and the particles in the liquid . At the respective distances from the incident location the scattered light exiting the sample is detected . The respective curves KI , K2 and K-3 correspond to the detected light at such distances .

For given substance a concentration, the light through the sample is scattered in a certain way resulting in a decrease , which is characteristic for a given substance concentration . Consequently, each substance concentration may comprise a different decrease in the signal of the measured values over the respective distances . By evaluating the difference in the detected signals between two given distances , one may obtain the concentration of the substance to be determined in the respective sample . This principle is applied to the glucose a measurement as mentioned above .

For such measurement several implementations of detector devices can be used . Figure 2 and Figure 3 illustrate an exemplary embodiment for such measurement devices suitable not only to detect and derive a glucose concentration in blood, but also for a variety of further measurements . The detector device 1 in Figure 2 comprises a substrate 5 , which is embedded in a housing 10 . Housing 10 also comprises a light emitting device 11 in form of an optoelectronic component or a lighting diode , LED . The lighting diode is configured to emit light of one or more wavelengths through an exit window 12 on the top surface of the housing 10 . Lighting diode 11 is also spaced apart from two light detecting components or photo diodes 20 and 25 , respectively . The two photo diodes 20 and 25 also spaced apart from each other . More particular , the distance between lighting diode 12 and the first photo detector 20 is given by d2 , the distance between diode 2 and second photo detector 25 is given by d3 + d2 . Hence , the distance between the LED 11 and the two photodetectors 20 and 25 are different .

An entry window 13 with a respective filter element is applied in front of the respective photo diodes 20 and 25 . The filter element is transparent for the wavelengths of light emitting diode 11 , but otherwise comprises a high absorption or reflection for wavelength outside that the respective frequency band . The entry windows will reduce the amount of ambient light being detected by the respective photo diodes 20 and 25 during the measurement cycle . In an alternative embodiment or also additionally, the light detecting elements may be sensitive to the wavelength, but otherwise insensitive . Furthermore housing 10 comprises a light blocking element 32 that is provided between the light emitting diode 11 and the photo diodes 20 and 22 , respectively . The lighter blocking element 32 provides an optical separation between the light emitting component and the light directing components .

Housing 10 further comprises a control and evaluation circuit 30 , which is connected to the light emitting component and related to directing components , respectively .

Figure 3 illustrates a similar embodiment of a detector device in accordance with the proposed principle . However , the detector device illustrated in Figure 3 shows a first light emitting component 11 and a second light emitting component 15 , which are spaced apart from a single light detecting component 20 . Similar to the previous embodiment , the distance between the light emitting component and the respective light detecting components are different .

The difference in length does also correspond to the optical path length, which is illustrated in the Figures 2 and 3 , given the referral number DI and D2 . The optical path length is the path inside the sample 2 , the light is traveling from the spot on the sample' s surface for the incident light to the location at which exiting light is detected . Apart from the obvious fact that the length of optical path DI is longer than the length of optical path D2 , there is a relation between the optical path DI and D2 and the distance between LED2 and the detector elements 20 and 25 , respectively .

Due to the fact that light intensity ratios and not absolute light strengths are evaluated in accordance with the proposed principle , it is sufficient to consider the known and measurable distances d2 and d3 .

For a good measurement , the shape and structure of the top surface of the housing that is in the particular the exit window in front of the light emitting component and the entry window in front of the detecting components 20 and 25 should be shape such that it is substantially light tight when a sample is placed upon the respective windows . In case , in which the sample is compressible , the sample should be a slightly pressed on the respective windows to further reduce any incident or ambient light from reaching the light detecting components . Likewise , the exit window is tightly arranged against the sample to prevent ambient light from entering the incident location at the entry sample surface .

Figures 4 to Figure 9 illustrate various results of measurements for a change of the glucose concentration in blood over time after digesting a sugar containing liquid . The various figures illustrate possible evaluation steps to be conducted by a control circuit in accordance with some aspects of the proposed principle . It has been found that the detected backscattered light shows a strong correlation between the glucose concentration and the time passed after digestion of a sugar containing liquid . The measurements are taken together with a reference measurement , illustrated in the Figures 4 to 9 by curves RK. The refence measurements RK are taken by conventional glucose measurement apparatus from Abbott® .

The measurements were taken at a resting person with a heart rate is determined to be approximately 1 . 2 Hz . Since the proposed optical measurements is purely optical and therefore non-invasive , a plurality of samples was measured and processed to obtain a plurality of data point with a frequency of one data point every 10 sec . Sampling rate was approximately 30 Hz , which is also inside the range of a typical PPG measurement . Duty cycle is approximate 10% . It should be noted in this regard that the data points will be affected by the optical path length change due to the blood level . The perfusion index is dependent on the glucose level and since the measurement points are taken at "high" or "low" blood level , the effect f the perfusion is included in the measurement . However, as this effect is present for the measurement at different distances , the overall effect may be partially compensated when evaluating as it will be explained below .

A background is obtained and subtracted from each sample . The background is measured during the OFF period . The background includes inherent dark-current of the detector as well as any ambient light , both of which may contribute to a photo-diode current , CCD-charge , voltage drop , or some other measurable quantity . The background is averaged with a sample measurement in between . The result is then used for this particular sample .

The figures illustrate the individual evaluated data points , but also the 5 min moving average and the 15 min moving average . The moving average was used to average outliers and individual measured data points in order to obtain a smoother curve . Depending on the evaluation, the measured data points are further processed to determine different correlations and best practice .

Figure 4 illustrates the results after evaluating the ratio of the processed signals at 2 mm and 4 mm . Both signals are divided to compensate for ambient light and other signal portion that do not originate from the scattering . Further , forming of the ratio of the overall signal ( that includes the DC portion and the AC portion originating from the perfusion ) will render the result more robust against variations . The result is given by (AC/DC ) intensity signal i / (AC/DC ) intensity signal 2 - The measurement is taken with green light that usually has a higher absorption and more interaction with the tissue . The y-axis on the left side shows the ratio in an arbitrary scale , the y-axis on the right side is the glucose level derived from the reference measurement .

The moving average on 5 min as well as on 15 min shows a strong correlation between time the measurement results . It basically follows , although it may be slightly delayed due to process of moving average . The peaks in curve K4 are an artifact resulting from the optical measurement and relate to 2n or 360 ° rotation in the measurement due to the change of the difference in the refractive index . This effect is reduced in Curve K5 with its longer moving average indicating that the peaks originate from the measurement .

Figure 5 illustrates a similar measurement but taken at a wavelength in the red spectrum . The reference curve RK in Figure 5 is equal to the one in Figure 4 . Again curves K4 and K5 follow the glucose concentration in blood, with curve K4 having two smaller yet recognizable maxima occurring at approximately the same time as for the curve K4 in Figure 4 .

Figure 6 illustrates the measurement result for a wavelength at 940 nm, whereas a ratio is firmed of the scattered signals detected at a distance of 2 mm and 4 mm, respectively . Similar to the other figures , the result of the moving average follows the refence curve and the corresponding glucose level . The initial peak visible at around 10 . 30 is either an outlier due to the , but some measurements indicate that the initial increase in the optical signal is faster than the respective reference measurement . This is due to the fact that the glucose level also strongly depends on the location at which the reference measurement takes place , while the optical measurement substantially determined in glucose level in the blood . For example , some it has been found that devices used for establishing the reference curve may measure the glucose level in the intermuscular tissue and/or outside larger blood vessel . The any increase of the glucose in the blood stream is delayed until it may reach a similar level in the intermuscular tissue and/or outside larger blood vessel . Such delay seems to be visible particularly during the initial phase .

Figures 7 and 8 represent the AC potion of the measured signal obtained within red spectrum, that is at wavelength of 637 nm . For a plurality of samples , the overall signal will vary slightly in response to the heartbeat . The difference between the maximum value and the minimum value during a single heartbeat if references as diffusion index . Usually, the perfusion index is given at approximately half of the heartbeat . Apart from the AC portion, one may also obtain the DC portion, that is the averaged signal over a number of heartbeats . The ratio between the AC portion to DC portion (AC/DC ) can be used for evaluating the substrate concentration at different distances . Alternatively, one can also use the DC portion or the AC portion separately .

Figures 7 and 8 represent the optical modulation, that is the AC portion and perfusion index . Figure 7 is measured at a distance of 4 mm; Figure 8 is measure at a distance of 2 mm. The AC portion also show a correlation between the glucose concentration and the obtained results . The AC portion may however contain arbitrary parts in the signal that originate from the measurement itself and not from the scattering at the substance to be detected . Hence , it is suitable to gauge the signal , by for example measuring the amount of incident light onto the sample .

Figure 9 finally is a measurement representing 1 /DC of a scattered signal with a wavelength of 637 nm at a distance of 4mm between the spot of incidence and the location of detection . LIST OF REFERENCES

1 detector device

2 sample 5 substrate

10 housing

11 light emitting component , LED

12 exit window

13 entry window 20 , 25 light detecting component , photo diode

30 control circuitry

KI measurement curve

K2 measurement curve

K3 measurement curve K4 , K5 measurement curve

RK reference curve

Claims

CLAIMS A method for determining a substance concentration in a sample comprising liquid containing particles , in particular glucose in blood, wherein a refractive index of the liquid is dependent on a concentration of the substance dissolved therein and a density of particles in the liquid is substantially constant , comprising the steps of :

- emitting a , -in particular periodic- first light pulse of at least one wavelength onto a first location of the sample containing the liquid;

- detecting at a second location a first light component scattered by the sample , the second location being distanced from the first location by a first distance ;

- detecting at a third location a second light component scattered by the sample , the third location being distanced from the first location by a second distance different from the first distance ;

- detecting at least at one of the second and third location a third light component during a duration, where no light is emitted;

- obtaining a first intensity signal from the first light component and the third light component ; obtaining a second intensity signal from the second light component and the third light component ;

- deriving a substance concentration or a change of substance concentration from the first and second intensity signal , in particular from a ratio of the first and second intensity signals . A method for determining a substance concentration in a sample comprising liquid containing particles , in particular glucose in blood, wherein a refractive index of the liquid is dependent on a concentration of the substance dissolved therein and a density of particles in the liquid is substantially constant , comprising the steps of :

- emitting a , -in particular periodic- first light pulse of at least one wavelength onto a first location of the sample containing the liquid; - emitting a, -in particular periodic- second light pulse of at least one wavelength onto a second location of the sample containing the liquid;

- detecting at a third location a first light component scattered by the sample , the third location being distanced from the first location by a first distance ;

- detecting at the third location a second light component scattered by the sample , the third location being distanced from the second location by a second distance different from the first distance ;

- detecting at least at the third location a third light component during a duration, where no light is emitted;

- obtaining a first intensity signal from the first light component and the third light component obtaining a second intensity signal from the second light component and the third light component ;

- deriving a substance concentration or a change of substance concentration from the first and second intensity signal , in particular from a ratio of the first and second intensity signals .

3 . A method for determining a substance concentration in a sample comprising liquid containing particles , in particular glucose in blood, wherein a refractive index of the liquid is dependent on a concentration of the substance dissolved therein and a density of particles in the liquid is substantially constant , comprising the steps of :

- obtaining a reference value associated with or corresponding to at least one of :

- an intensity at a predefined distance ;

- an signal corresponding to a light portion received at a predefined distance from a light source ;

- a function linking an intensity signal to distance from a light source ;

- detecting at a second location a first light component scattered by the sample , the second location being distanced from the first location by a first distance , wherein optionally the first distance is different from the predefined distance ;

- detecting a third light component during a duration at the second location, when no light is emitted;

- obtaining a first intensity signal from the first light component and the third light component ;

- deriving a substance concentration or a change of substance concentration from the reference value and first intensity signal , in particular from a ratio of the reference value and first intensity signals . Method according to any of the preceding claims , wherein the first and/or second light pulse comprises a periodicity between 20 Hz and 500 Hz , an in particular between 50 Hz and 200 Hz and particular above 75 Hz ; and wherein optionally, the first and/or second light pulse comprises a duty cycle in the range of 1/20 to 1 /5 of the period . Method according to any of the preceding claims , wherein a time difference between emitting the first light pulse and emitting the second light pulse is less than 1 second and particularly between 10 ms and 250 ms and more particularly between 30 ms and 100 ms . Method according to any of the preceding claims , wherein a direction from the first location to the second location is different to a direction from the first location to the third location . Method according to any of the preceding claims , wherein the duration during which the third light component is detected is longer than a duration during which the first and/or second light component is detected . Method according to any of the preceding claims , wherein detecting the first light component and/or detecting the second light component comprises obtaining a plurality of samples , and subsequently combining at least some of said samples . Detector device for determining a substance concentration in a sample comprising liquid containing particles , in particular glucose in blood, wherein a refractive index of the liquid is dependent on a concentration of the substance dissolved therein and a density of particles in the liquid is substantially constant , said detector device comprising : a housing having at least one optoelectronic component and at least one light detecting component , wherein the at least one light detecting component within the housing is optically separated from the light emitting device ; wherein said at least one optoelectronic component is configured to emit light through an exit window onto a sample ; and said at least one detecting component is configured to detect two light components corresponding to emitted light scattered through the sample , wherein said two light components correspond to different path length of light travelling through the samples ; a control circuit coupled to the at least one optoelectronic component and at least one light detecting component and configured to obtain a first signal from the at least one detecting component corresponding to a detected first light component , a second signal from the at least one detecting component corresponding to a detected second light component and a third signal from the at least one detecting component corresponding to a detected third light component , whereas the third light component is detected while the at least one optoelectronic component is not emitting ; said control circuit further configured to derive a first intensity signal from the first and third signal and a second intensity signal from the second and third signal ; said control circuit further configured to derive a substance concentration from o the first and second intensity signal , in particular from a ratio of the first and second intensity values ; or o a reference value stored in a memory and one of the first and second intensity signals or values derived therefrom . The optoelectronic device according to claim 9 , wherein the reference value is derived by at least one of : an individual previous measurement ; a statistical value , wherein optionally the statistical value is dependent on at least one of o body mass index ; o age , gender , height and weight ; and o s kin type . Detector device according to claim 9 or 10 , wherein a distance between the at least one optoelectronic component and a first of the at least one light detecting component is different to a distance between the at least one optoelectronic component and a second of the at least one light detecting component . Detector device according to claim 9 or 10 , wherein a distance between a first of the at least one optoelectronic component and the at least one light detecting component is different to a distance between a second of the at least one optoelectronic component and the at least one light detecting component . Detector device according to any of claims 8 to 12 , wherein the at least one optoelectronic component and the at least one light detecting component are arranged substantially in the same plane . Detector device according to any of claims 9 to 13 , wherein the at least one optoelectronic component and the at least one light detecting component are arranged in two different , optionally substantially parallel planes , wherein optionally the sample is placeable in a light path between the two different planes . Detector device according to any of claims 9 to 14 , wherein the at least one light detecting component comprises a light filter comprising a low transmittance in a frequency spectrum different from a light spectrum emitted by the at least one light emitting component .